Wilms tumor (WT) is a childhood kidney tumor which, due to its development in early childhood and its generally euploid genome, is a valuable model for investigating the role of genetic alterations in tumorigenesis in the absence of wide spread aneuploidy and confounding environmental effects. WT occurs both sporadically and in a familial context. Familial predisposition to WT is heterogeneous; the 11p13 WT gene, WT1, can be excluded as the predisposing gene in most WT families as can a 17q region which is linked to predisposition in a large French Canadian family. These data demonstrate the existence of a gene(s) that confers tumor predisposition in most WT families. We have identified a region of 19q13.4 (FWT2) that is genetically linked to predisposition in several large WT families. We have also identified tumor-specific loss of heterozygosity (LOH) at FWT2. Significantly, for individuals from two WT families which are not genetically linked two FWT2, tumor-specific LOH at FWT2 is nevertheless observed. From these data we hypothesize that in WT families, the rate limiting steps in tumorigenesis involve alterations at least two loci. These alterations are a combination of heritable mutations, as identified by genetic linkage analysis, and somatic alterations as detected by LOH or mutational analysis. The goals of the proposed study are 1) to evaluate the occurrence of interacting germline and somatic alterations at several genomic regions in tumors from 19q-linked and non-19q-linked WT families, and 2) to sub-localize and isolate the FWT2 gene using the vast resources of physical and genetic mapping data and genomic and cDNA clones that exist for chromosome 19. Normal and tumor tissue from members of WT families will be assessed for 19q linkage, WT1 mutations. LOH, 19q alterations, and alterations at specific candidate FWT2 genes. Identification of the genes affected by either germline or somatic alterations in familial WT will enable us to define biochemical pathways abrogated by these alterations in familial WT will enable us to define biochemical pathways abrogated by these alterations in familial WT will enable us to define biochemical pathways abrogated by these alterations and determine whether 6the alterations affect the same, or different, pathways. Comparison of these data with those from the sarcoma families (Projects 1 and 4) will provide further insight into the role of genetic alterations in both childhood and adult-onset tumors.